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Several recent clinical trials have established that reboxetine, a new selective norepinephrine reuptake inhibitor (selective NRI), is effective and safe for the treatment of major depression. However, the effects of reboxetine on specific symptoms of anxiety, agitation, and insomnia have not been reported. Data were obtained from nine short-term, double-blind, randomized clinical trials in patients with major depression. After initial titration, patients received reboxetine 8 to 10 mg per day. The effects on specific HAM-D symptoms of agitation, anxiety, and insomnia were compared between reboxetine- and placebo-treated patients. In addition, the incidence of treatment-emergent agitation, anxiety, and insomnia side effects with reboxetine were examined. Compared with placebo, the proportion of patients with improvement on the HAM-D agitation item and the HAM-D anxiety and insomnia factors from baseline was significantly greater with reboxetine at most assessment intervals. In general, the incidence of agitation- or anxiety-related side effects was comparable with reboxetine and placebo. Although reboxetine was associated with a significant (p < 0.05) increase in treatment-emergent insomnia reported as an adverse effect during the first week of treatment, very few reports of insomnia were made at subsequent evaluations. The incidence of treatment-emergent agitation or anxiety was comparable between treatment groups.

This multicenter study compared the efficacy and safety of citalopram and placebo in a population of moderately to severely depressed patients with melancholia. This randomized, double-blind, parallel-group study compared citalopram (flexible dose; 20-80 mg/day) with placebo in 180 psychiatric outpatients with a DSM-III diagnosis of major depression or bipolar disorder, depressed, who also met DSM-III criteria for melancholia. Following a 1-week placebo washout period, patients meeting study entry criteria were randomized to 4 weeks of double-blind treatment with either citalopram or placebo. Efficacy measures included the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions (CGI) Scale, and the Zung Self-Rating Depression Scale. Patients treated with citalopram showed significantly greater improvement at endpoint than placebo patients on the HAM-D, CGI, and Zung scales. On the HAM-D, citalopram patients exhibited significantly greater improvement than placebo patients after 1 week of double-blind treatment and at all subsequent study visits. Endpoint analyses of the HAM-D subscales demonstrated that citalopram produced significant improvement of the psychomotor retardation, cognitive disturbance, sleep disturbance, and melancholia symptom clusters. Nausea, dry mouth, somnolence, dizziness, and increased sweating were reported at higher rates by citalopram-treated patients than by placebo-treated patients, but there were no significant citalopram-placebo differences in the incidence of activation (e.g., anxiety, nervousness, insomnia) or sexual dysfunction. Analysis of electrocardiograms, vital signs, and laboratory tests did not reveal any clinically significant effects of citalopram treatment. The results of this study indicate that citalopram is safe and effective in the treatment of depressed patients with melancholia, and is associated with a favorable side effect profile and a potentially rapid onset of action.

This study was designed to examine the efficacy and safety of sertraline as a treatment for premature ejaculation. Fifty-two heterosexual male patients with self-reported premature ejaculation were randomly assigned to receive either sertraline or placebo. After a 1-week placebo washout period, the dose was titrated during treatment weeks 1 to 3 from 50 to 200 mg of sertraline per day until clinical response was optimal or dose-limiting adverse experiences emerged. Medication was maintained at this level through week 8. The primary outcome measures used to assess efficacy included patient assessment of time to ejaculation (from penetration), number of successful attempts at intercourse, and incidence of ejaculation during foreplay. Sertraline treatment produced significant improvements relative to placebo in time to ejaculation and number of successful attempts at intercourse, as well as overall clinical judgements of improvement. Medication was well tolerated by most patients. Because sertraline therapy caused significant prolongation of time to ejaculation, this agent may be useful as a treatment for selected patients with premature ejaculation.

Because a substantial number of patients with insomnia take hypnotics for extended periods, maintenance of effectiveness and the effects of withdrawal following long-term use are critical issues. In this multicenter, single-blind study, patients between 18 and 60 years of age (mean, 42 years) received placebo for 4 to 7 nights, followed by 12 weeks of nightly treatment with zolpidem 15 mg, followed by placebo for 1 withdrawal week. If adverse events occurred, the study design allowed for a dose reduction to 10 mg. Efficacy was evaluated subjectively using the Clinical Global Impression scale at the end of the placebo run-in period and at the end of weeks 2, 4, 8, and 12 and placebo week 13. In addition, patients completed self-reports, describing their sleep before each visit. Of the 229 patients who received zolpidem, 155 patients completed all 12 weeks of treatment. Thirty-three patients had their dose decreased from 15 mg to 10 mg at some time during the study. Adverse effects led to withdrawal in only 8% of the patients initially enrolled. The incidence of side effects was considerably higher with the 15-mg dose compared with the 10-mg dose. Despite the prolonged use of higher than currently recommended doses of zolpidem, no evidence of rebound insomnia was reported. In addition, there was no evidence of drug tolerance throughout the 12 weeks of drug administration. In agreement with recommendations of numerous previous studies, the 10-mg dose was found to be safe during the 12-week treatment period.

BRAY, GEORGE A., GEORGE L. BLACKBURN, JAMES M. FERGUSON, FRANK L. GREENWAY, ADESH K. JAIN, CARL M. MENDEL, JOSEPH MEN-DELS, DONNA H. RYAN, SHERWYN L. SCHWARTZ, MONTE L. SCHEINBAUM, AND TIMOTHY B. SEATON. Sibutramine produces dose-related weight loss. Obes Res. Objective Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. Research Methods and Procedures Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. Results Weight loss was dose-related and statistically significant vs. placebo (p

The functional role of cholecystokinin in the central nervous system is unknown. The tetra peptide CCK-4 was previously observed to induce panic attacks in a majority of normal volunteers and patients with panic disorder. Furthermore, it had been demonstrated that pretreatment with 10–50 mg of L-365,260, a selective CCK B antagonist, blocked CCK-4 induced panic in patients with panic disorder. Therefore, the present multicenter, placebo-controlled, double-blind trial was designed to investigate the efficacy of L-365,260, a CCK B antagonist, in patients with panic disorder with or without agoraphobia. Following a 1-week, single-blind placebo period, 88 patients were randomized to double-blind treatment in which they received either L-365,260, 30 mg qid, or placebo for 6 weeks. At the dose tested, there were no clinically significant differences between L-365,260 and placebo in global improvement ratings, Hamilton anxiety rating scale scores, panic attack frequency, panic attack intensity, or disability measures. The possible reasons for lack of effect with L-365,260 are discussed.

The authors present a clinical approach for predicting and using plasma concentrations of tricyclic antidepressants in the treatment of depressed patients. They review the pharmacokinetics of this group of drugs and their side effects and toxicity. There is a suggested therapeutic range for plasma concentrations of imipramine, amitriptyline, and nortriptyline; more definitive studies are needed to determine the necessary plasma levels for achieving clinical response with the other tricyclic antidepressants (desmethylimipramine, protriptyline, doxepin, clomipramine, impiramine N-oxide, and butriptyline). A more thorough knowledge of the clinical pharmacokinetics of tricyclic antidepressants should lead to more rational use of these drugs, with a higher response rate and fewer adverse reactions.

The relationship between the lithium ratio (ratio of lithium in blood cells to that in plasma) and plasma lithium concentration was examined in a group of male inpatients taking lithium carbonate for affective disorders. The lithium ratio was found to increase in the majority of these patients as plasma lithium concentration increased. However, the magnitude of variation of the lithium ratio with plasma lithium concentration observed in these patients is not sufficient to seriously affect the value of determining the lithium ratio in the clinical situation.

The efflux of 22Na from erythrocytes was measured in vitro under experimental conditions such that rate constants due to efflux either by active transport, passive diffusion, or exchange diffusion could be calculated. No significant differences were found in the rate constants for 22Na efflux between seven male bipolar depressed patients and eight male control subjects, who had no personal or family history of psychiatric illness. Treatment of patients with lithium carbonate either for less than one week or for 4–5 weeks produced no changes in the rate constants describing the efflux of 22Na from red cells. Also, addition of 1mM LiCl in vitro did not alter the active transport of 22Na from erythrocytes. These data provide no evidence for either an abnormality in 22Na transfer across the red cell membrane of bipolar depressives or an effect of the lithium ion upon such transfer.

Plasma and erythrocyte cations (sodium and magnesium) were studied in groups of patients with an affective disorder and in normal subjects. Baseline determinations were obtained before initiation of treatment for mania or depression. In a subgroup of patients, sequential measurements of cations were made during treatment with lithium carbonate. No differences were found in intraerythrocyte sodium or magnesium among any of the patient groups and controls. Patients with a primary affective disorder had significantly higher plasma sodium than control subjects. Neither baseline cation concentrations nor changes in cation concentration during treatment with lithium correlated with treatment response. Gender was shown to be a significant variable affecting intraerythrocyte cation concentrations.

SynopsisUrinary free Cortisol (UFC) excretion was determined in 60 depressed inpatients and in 35 psychiatric inpatients with other disorders. The depressed patients had high daily UFC values, while the other patients excreted normal amounts. Over 40% of the depressed patients had UFC excretions in the range seen in Cushing's disease, while only 6% of the other patients excreted such high amounts of Cortisol. Age and sex differences did not account for the results. Among the depressed patients those with depressive neuroses excreted less than unipolar or bipolar depressives. Following treatment, more normal UFC excretion was found in depressed patients. The estimation of UFC and its clinical utility are discussed in detail. UFC determination is a simple and informative indicator of adrenal cortical activation and its application to psychoendocrine studies is recommended.

The role of a broad range of life events, especially those viewed as stressful, in the genesis of somatic illnesses or psychiatric disturbances is a subject of considerable interest. Recently attempts have been made to develop quantitative measures of life events and to explore the relationship between the ‘amount’ of life events and/or stress and illness in a general population (Rahe et al., 1968; Rahe et al., 1970): for example, The Social Readjustment Rating Questionnaire (SRRQ) (Holmes and Rahe, 1967). In the development of this scale a list of 43 life events was presented to a sample of 394 subjects. Marriage was arbitrarily assigned a value of 500, and the subjects were asked to compare the amount of relative readjustment they would anticipate from the other events. Means and item rankings (Masuda and Holmes, 1967) have been reported to be relatively consistent in groups of different age, sex, marital status, education, social class, generation American, religion, race and cultural background (Holmes and Rahe, 1967). These findings have been found reliable with patients on our unit and in a group of medical students (Mendels and Weinstein, 1972). Paykel et al. (1971) performed a study of weightings of a list of life events and obtained weights which were highly significantly correlated for the 14 items that were identical to those found on the SRRQ. They tested a mixed group of psychiatric patients and found that in general those events defined as ‘exits’ were scaled high, whereas events defined as ‘entrances’ had lower values.

Lithium ions accumulated consistently in the pituitary and thyroid of rats at concentrations significantly greater than in plasma. There was also a significant, although lower, accumulation of Li + in the adrenal gland. No accumulation of lithium ion was noted in the testis or in the ovary. The possible significance of these findings with regard to some of the side effects of lithium carbonate treatment is discussed.

Interest in biogenic amine function in affective disorders has stimulated a variety of research strategies including the measurement of hormonal response to a variety of stimuli as an indirect method of investigating the integrity of aminergic function in clinically depressed patients. Apomorphine and levodopa are known to stimulate growth hormone release via a dopaminergic pathway in median eminence. Administration of these agents to groups of depressed patients and age, sex-matched normal control subjects did not indicate any significant abnormality in this dopaminergic system.

The effect of a variety of psychotropic drugs, given to rats repeatedly over 16 days, on the number of beta-adrenergic receptor binding sites in cerebral cortex was measured. Labelled dihydroalprenolol, [ 3 H]-DHA, was used to measure beta-adrenergic binding sites. Both tricyclic antidepressants (amitriptyline, chlorimipramine, desmethylimipramine and nortriptyline) and monoamine oxidase inhibitors (nialamide and tranylcypromine) lowered [ 3 H]-DHA binding significantly. Repeated treatment of rats with the antidepressant. iprindole. produced the same effect as did treatment with bupropion. However, the experimental antidepressant mianserin did not reduce [ 3 H]-DHA binding nor did 11 other psychoactive compounds including chlorpromazine, diazepam, l -DOPA, tripelennamine and cocaine. The reduction in [ 3 H]-DHA binding produced by nialamide or iprindole treatment was due to a reduction in the maximum number of beta-adrenergic receptor binding sites. Drug treatment-induced lowering of [ 3 H]-DHA binding sites in cerebral cortex appears to have utility as a pre-clinical test for antidepressant drugs.

For the past decade there has been extensive interest in the hypothesized association between brain amine function and disturbances in mood (either depression or mania). The more influential theories have postulated that clinical depression is associated with a decrease in aminergic function (either norepinephrine, dopamine or serotonin) while mania is associated with increased activity of these amines. This essentially ‘bipolar’ approach has tended to dominate most studies in this area. Evidence supporting these theories has been extensively reviewed (11, 61, 70) and need not be detailed here.

18 hospitalized male depressives were treated with imipramine hydrochloride for 28 days. Prior to initiating treatment, each patient completed the Minnesota Multiphasic Personality Inventory (MMPI). At the end of the treatment period, the patients were divided into groups of responders and nonresponders based on the change in their Hamilton Depression Rating Scale scores. The Imipramine Response Scale - Male (IRS-M) was scored for each patient and the ability of the scale to predict response or nonresponse in our sample of patients was examined. There was no evidence that the IRS-M was better than chance in its ability to predict response.

Midazolam (15 mg) was compared with temazepam (30 mg) in a randomized, double-blind, parallel group study. An initial screening period was followed by 3 days of placebo baseline, 4 to 12 weeks of nightly oral use of the medication and a 4-day placebo withdrawal period. One hundred seventy-five patients with chronic insomnia participated in this multicenter outpatient study. Because the elimination half-life of midazolam, a new trizolobenzodiazepine hypnotic, is short (1.3-2.2 hr) compared to temazepam's (12-16 hr), more problems with tolerance and rebound insomnia were expected to occur. Hypnotic efficacy (increased total sleep time, decreased wake time, and decreased sleep latency) was demonstrated for both medications over the entire 3-month period without the development of tolerance. In fact, if anything, efficacy increased with time on medication, suggesting possible facilitation or "inverse tolerance" effect. On withdrawal, sleep was improved compared with baseline, suggesting partial resolution of the insomniac condition rather than rebound insomnia. These effects were both statistically and clinically significant for midazolam, with 16% to 50% improvement in sleep measures. The results of this study suggest that patients with chronic insomnia may benefit from 30 to 90 days of treatment. A three-factor model that separates pharmacologic from behavioral and psychologic effects of hypnotics was proposed to explain these results in part.

Tricyclic antidepressant plasma levels were measured in patients and healthy subjects after a single dise of desmethylimipramine (DMI) or imipramine (IMI) and after chronic dosing to steady states. Tricyclic plasma levels measured 24 hr after the single oral dose correlated with steady-state plasma levels. In patients receiving DMI there was a correlation (r = 0.97, n = 10) between 24-hr and steady-state DMI levels, while in normal subjects receiving IMI the correlation was r = 0.92 (n = 20) between 24-hr and steady-state total tricyclic levels (IMI plus its metabolite, DMI). These results suggest the possibility that after a test dose of tricyclic antidepressant, a patient may be put on a "therapeutic" dosage regimen without delay.

The effects of parachlorophenylalanine, a serotonin synthesis inhibitor, on the sleep of a subject receiving methadone was studied. Gradually increasing doses of PCPA from 250 mg./24 hour to 2,500 mg./24 hour had no discernible effect on actual sleep time or on the amount of REM sleep contrary to previous reports. On the other hand, all REM-associated events were affected. There was a decreased time to REM onset, a decrease in the sleep cycle, a decrease in phasic REM (per cent REM epochs with eye movements), and a decrease in extraocular spike activity during REM sleep (but not during NREM sleep). There was also a significant increase in delta wave sleep which coincides with urinary 5HIAA values. This leads us to speculate that there may be a critical level of serotonin (perhaps relative to other brain amines) for optimal sleep and that levels of serotonin above or below this result in a decrease in delta sleep.

Alterations in cation concentration, transport or distribution play an important role in the regulation of neuronal function and may contribute to the production of abnormal mood states such as depression or mania. The effectiveness of the cation, lithium, in the treatment of affective disorders has spurred increased interest in and investigation into cation metabolism in these illnesses. The findings from investigations of sodium, magnesium and lithium are reviewed and the idea is advanced that the erythrocyte can be used as a model for the neuronal transport and concentration of these cations. Evidence is presented that the intraerythrocyte lithium concentration, as expressed by the Lithium Ratio, is significantly different between unipolar and bipolar groups of patients. Intraerythrocyte sodium and magnesium do not appear to differ between diagnostic groups or between manic and depressed patients and controls. However, sex is an important variable affecting the concentrations of all three of these cations and this factor must be taken into account in future studies of cation metabolism in affective disorders.

LITHIUM carbonate is now widely used for the treatment of mania,ls2 the prophylaxis of recurrent mania and depression2-4 and, to an extent, in the treatment of selected depressed patients. 5- 7 There is a clear trend towards the increased use of lithium for more patients and for longer periods of time.s Since depressed and manic patients have a significant sleep disturbance and. as it has been suggested that there may be significant associations between these sleep changes and both the clinical syndromes and the antidepressant drug effects,s-13 it seemed important to determine the effect of lithium on sleep (both acutely and chronically). Further, if lithium, which is now being used chronically for many patients, were to adversely affect sleep, then these patients may experience long-term sleep alterations of unknown implications. It is also of interest to determine what, if any, are the correlations between lithium’s therapeutic and prophylactic effects and its influence on the disturbed sleep pattern of these patients. Depressed patients (as a group) have a reduction in total sleep time, more awakenings during the night and less stage 4 sleep. 11, 14- 21 In addition, Mendels and Hawkins17,22 have reported that depressed patients take longer to fall asleep and wake significantly earlier in the morning and have increased amounts of stage 1 sleep. Reports on the amount of stage 1 REM sleep obtained by depressed patients are conflicting. Some studies report a reduction in REM sleep during depression, *I48 17* 20, 23-25 others report normal or even slightly increased REM sleep time with depression26p 27 with an earlier REM sleep onset1s,26 and an increase in phasic REM sleep elements such as eye movements. l s Later reports by MENDELS et aLa 2s* 3o likewise reflect a relatively high percentage of REM sleep as well as a pressure to achieve REM sleep in some (but not all) depressed patients. Two previous studies31* 32 of the effects of lithium carbonate on sleep offer apparently contradictory results, although the different findings may be a function of the dose administered and the subjects studied. BREBBIA et al. 31 administered 750 mg/24 hr lithium carbonate for 8 days to three control subjects and to three manic patients with plasma levels ranging between 0.34 and 0.46 mEq/l. The plasma levels are below those regarded as being in the therapeutic or prophylactic range. 2,8 They reported no uniform change in sleep pattern associated with the drug. KUPFER et al.,32 on the other hand, reported a significant increase in delta wave sleep (stages 3 and 4 combined) and a significant decrease in stage 1

SummaryIn an investigation of the relation between life events (stressors) and illness, 87 medical students reported on a prospective basis their health and life events history over a three year period. There were a few positive findings, e.g. that subjects who reported more life events during the period also reported more illnesses during that period. Overall, however, the study showed a lack of statistically significant association between life events and illness.

The short-term safety and hypnotic efficacy of 15 mg of quazepam was compared with that of placebo in a double-blind study in sixty out-patients with insomnia. All patients received placebo for 3 consecutive nights to establish a baseline; for the next 5 nights thirty patients received quazepam and thirty received placebo. The results indicated that quazepam was significantly more effective than placebo in terms of quantity and quality of sleep and that quazepam was effective on the first night. Despite having a marked hypnotic effect, quazepam was not different from placebo in terms of hang-over effects (i.e., ease in awakening and alertness) the following morning. Treatment-related adverse experiences were reported by ten patients who received quazepam and by five who received only placebo. The most frequently reported adverse experience was daytime somnolence. This study demonstrates that quazepam, in a 15 mg dose, is an effective, rapidly acting, oral hypnotic agent with a low incidence of adverse effects.

Forty-two outpatients with major depressive disorder were treated with oral fezolamine in a 6-week, three-center open-label study. Therapy was initiated at 100 mg/day; thereafter dosage was increased based on the response of the patient. Maintenance dosage usually ranged between 100 and 450 mg/day. Clinically significant improvement relative to the patient's prestudy state was observed after 2 weeks in both patient and physician-rating scales. Fifty-five percent of patients improved their Hamilton Psychiatric Rating Scale for Depression (HAM-D) scores by more than 50%. The median dose associated with a clinically significant response was 245 mg/day. Five of the 6 patients who dropped out did so because of gastrointestinal adverse effects. The most common adverse effects were nausea (36%), headache (29%), constipation (26%), and dry mouth (24%).

The effect of repeated administration of monoamine oxidase inhibitors or serotonin agonists on [ 3 H]-serotonin binding and serotonin concentrations in rat cerebral cortex was examined. Five days of clorgyline administration, which alone caused a significant reduction in [ 3 H]-serotonin binding, was unable to do this in animals pretreated with drugs that deplete brain serotonin. Pretreatment of rats with alpha-methyl- para tyrosine did not block the clorgyline-induced reduction in [ 3 H]-serotonin binding. Repeated treatment of rats with nialamide also lowered [ 3 H]-serotonin binding and the return of binding sites to control values was correlated temporally with the return of the serotonin concentration to control values. Repeated administration to rats of the serotonin agonists, quipazine or TFMPP, produced a decrease in [ 3 H]-serotonin binding. Both the clorgyline and serotonin agonist-induced reduction in [ 3 H]-serotonin binding were due to a significant reduction in the maximum specific binding capacity with no change in the apparent binding constant. The data presented here are consistent with the hypothesis that MAO inhibitors reduce [ 3 H]-serotonin binding indirectly, by increasing over time the exposure of serotonin receptors to the indolealkylamine.

When lithium carbonate is administered to individuals, there is considerable intersubject variation in the extent of accumulation of Li+ by erythrocytes. The primary reason for this is differences in the activity of a Li+-Na+ counterflow system, which, under clinical conditions, removes Li+ from the cell. It appears that some bipolar patients accumulate more Li+ in their red cells than either unipolar depressives or normal controls. The precise clinical characteristics of the bipolar patients who accumulate relatively large amounts of erythrocyte Li+ need to be clarified in future research. Finally, the measurement of red cell concentrations of Li+, in addition to the usual plasma measurement, can be used as an indicator of patient compliance.

• Increasing attention has been given to the significance of intra-cellular concentrations of the lithium ion in patients treated with this drug. The erythrocyte has been the most common cell investigated because of its accessibility and certain similarities between the ion transport mechanisms of this cell and the neuron. Intraerythrocyte lithium is expressed as the ratio of lithium in the cell to the plasma lithium concentration (lithium ratio). The lithium ratio has been reported to be related to a number of clinical variables, including treatment response, clinical state, side-effects, toxicity, diagnosis, and electrophysiological effects. We have investigated the lithium ratio in a large series of patients with a primary affective disorder and in a smaller control group. We found a significantly higher mean lithium ratio in the bipolar diagnostic group than in the unipolar and control groups. There was a trend, not statistically significant, in the unipolar and bipolar groups for females to have higher lithium ratios than males. While not diagnostic, the lithium ratio appears to be another biological variable where bipolar patients, as a group, differ from normals and others with an affective disorder.

SummaryFifty-six psychiatric patients were interviewed to obtain a record of life events preceding admission to hospital, using a modified version of the Schedule of Recent Experiences. Two control groups were studied for comparison: medical and surgical in-patients and a ‘normal’ population studied independently by Myers. Psychiatric patients reported a significantly larger number of events than the medical-surgical patients, who, in turn, reported significantly more events than the ‘normal’ population. There were no significant differences in the specific life event histories between groups.

The movement of the lithium ion (Li+) across the membrane of intact erythrocytes incubated in vitro was assessed under two different experimental conditions in which such transfer occurred primarily due to the activity of a lithium-sodium countertransport system. The 13 subjects on whom the in vitro procedures were done subsequently received lithium carbonate for 14 to 56 days, and the extent of accumulation of Li+ by erythrocytes in vivo was measured. While both in vitro procedures yielded data that correlated with the extent of accumulation of Li+ by erythrocytes in vivo, a system measuring the efflux of Li+ from Li+-loaded cells produced a much higher correlation (0.976). The magnitude of this correlation suggests that this in vitro system can be used for further investigations into the relevance of the erythrocyte accumulation of Li+ to the pathogenesis and treatment of affective disorders.

• A reliability study of a life events questionnaire administered to 117 pairs of respondents indicated that a "significant other" (family member or friend) added approximately 29% new information to that gathered from the patient alone. A validity check of this information with a "knowledgeable" third party confirmed approximately 80% of the events reported by the subjects and significant others. The findings suggest that studies designed to collect information about the occurrence of specific life stressors would obtain more reliable and no less valid data from separate interviews of patients and significant others, and the pooling of the positive responses obtained from these two sources.

To evaluate the hypothesis that clinical depression is associated with reduced brain biogenic amine activity, the behavioral effects, in man, of drugs that deplete the brain of biogenic amines were reviewed. The behavioral changes associated with reserpine administration were interpreted as being primarily a psychomotor retardation-sedation syndrome, due perhaps to a dopamine deficiency, and would not be an adequate model for clinical depression. In susceptible persons, particularly those with a prior history of depression, this psychomotor retardation-sedation might be sufficient to trigger a depression-like episode. More selective amine depletion, produced either by alpha-methyl-paratyrosine or by parachlorophenylalanine is not associated with depression. Yet, these drugs produce a more consistent and greater reduction in amine metabolite concentrations than that reported to occur in depressed patients. In light of this, it is suggested that the depletion of brain norepinephrine and dopamine, or serotonin, is, in itself, not sufficient to account for clinical depression.

Tri-iodothyronine (T3; 15 μg) was administered to rats, alone or in combination with imipramine (20 mg/kg), for 5 days. The net synthesis of [3H]-cyclic AMP in cerebral cortex slices of animals so treated and control rats was then measured. The dose-dependent stimulation of [3H]-cyclic AMP by norepinephrine (NE) was significantly reduced in imipramine-treated rats. Tri-iodothyronine treatment had no effect on the enhanced net synthesis of [3H]-cyclic AMP produced by NE. In cortex slices of rats given both T3 and imipramine, NE produced less stimulation of [3H]-cyclic AMP than in control rats. The magnitude of this inhibitory effect was less than that observed in animals treated with imipramine alone. In vitro addition of imipramine to the cortex slice preparation reduced the stimulation of [3H]-cyclic AMP caused by NE; treatment of rats with T3 did not modify this inhibitory effect of imipramine in vitro. Isoproterenol produced significantly less stimulation of [3H]-cyclic AMP net synthesis than did NE; imipramine added in vitro had no effect on the stimulation produced by isoproterenol. It is concluded that the reason for the enhanced clinical effect of imipramine when given together with T3 is not due to the hormone exaggerating the effect of the antidepressant on NE stimulated adenylate cyclase. Furthermore, for NE to produce maximal stimulation of [3H]-cyclic AMP, uptake of the catecholamine is necessary.

SynopsisPreliminary data from the National Institute of Mental Health – Clinical Research Branch Collaborative Program on the Psychobiology of Depression dealing with the human growth hormone (hGH) response to the Insulin Tolerance Test (ITT) during the pre-treatment (drug-free) period of the study are presented in this paper. Data are reported for 54 unipolar depressed, 21 bipolar depressed, and 40 normal control subjects, who represent approximately 50% of the final subject sample to be studied. In this population the unipolar depressed subjects showed a significantly greater resistance to insulin-induced hypoglycaemia than bipolar and control subjects. After applying the inclusion/exclusion criteria necessary to interpret hGH responses accurately, the data from only 54 subjects were acceptable. Mean peak hGH concentrations were not significantly different among the three groups. There was, however, a significant difference in the distributions of the hGH peak response, with the bipolar depressed population demonstrating greater variability in response than unipolar and control populations. These findings are discussed as they relate to previous reports and theoretical considerations.

Clonazepam (CZP) was measured in the plasma of eight subjects for 48 hr after a 0.03-mg/kg oral dose. After pretreatment for 19 days with phenytoin (DPH, 4.3 mg/kg/day), plasma CZP concentrations were determined in the same subjects after another 0.03-mg/kg oral dose of CZP. The same protocol was followed in eight additional subjects using phenobarbital (PB, 1.4 mg/kg/day) instead of DPH. DPH pretreatment lowered mean plasma CZP concentration in 8 of the 12 time points. DPH pretreatment increased CZP clearance by 46% to 58% and decreased CZP half-life (t½) by 31%. Both changes were statistically significant. After PB pretreatment the mean plasma CZP concentration was lowered by an average of 11%, but the decrease was statistically significant for only 1 of the 12 time points. PB decreased mean CZP t½ by 11% and increased CZP clearance by 19% to 24%, but only the increase in clearance was statistically significant. Both DPH and PB increased CZP clearances and decreased the areas under the plasma concentration-time curves without altering the volumes of distribution. This observation is consistent with induction of CZP metabolism. The overall effect of DPH (4.3 mg/kg/day) was greater than the effect of PB (1.4 mg/kg/day). Neither the DPH or PB had a significant effect on the extent of CZP protein binding. Clinical Pharmacology and Therapeutics (1980) 28, 368–375; doi:10.1038/clpt.1980.175

A sociodemographic and clinical picture is presented of 82 depressed subjects who had an unequivocal response or lack of response to treatment with amitriptyline or imipramine. Patients with less severe depressive illness were found more likely to respond to treatment, while those with psychotic features were more likely to be treatment resistant. Sociodemographic and other prior and current clinical course variables were not predictive of treatment response in depressed patients.

SynopsisCerebrospinal fluid (CSF) cortisol levels were examined in a total group of 65 patients. Those who were not depressed (ND), and those suffering from depressive neuroses (DN) had marginally elevated values. Patients with unipolar depression (UD) and bipolar depression (BD) had levels twice as high as the ND and DN patients. Psychotic UD and BD patients had the highest values, three to four times as high as the ND and DN subjects. A significant reduction of CSF cortisol levels was observed following treatment and recovery. Manic patients had moderately elevated CSF cortisol values. The CSF results were in good agreement with plasma total cortisol levels and with urinary free cortisol excretion. Age and sex effects were not responsible for the observed differences; similar results were found in patient subgroups studied in Australia and in the United States. Preliminary equilibrium dialysis data are presented for plasma and CSF cortisol binding. CSF cortisol was 20% bound and 80% free. Plasma free cortisol levels were in good agreement with CSF free cortisol values. Depressed patients have increased tissue and central nervous system (CNS) exposure to free, physiologically active glucocorticoids. The appearance of severe depressive symptoms which manifest a diurnal rhythm may be determined in part by excessive CNS exposure to glucocorticoids.

The use of lithium in the treatment of depression remains controversial. One reason for this is that lithium was initially demonstrated to be effective in the treatment of mania. The most prevalent theories about affective disorders have tended to view depression and mania as biochemically and clinically opposite states and there has consequently been some reluctance to acknowledge the possibility that a single drug might be effective in treating both conditions. In addition, there are several effective antidepressant therapies available, whereas the treatment of mania, prior to the introduction of the lithium ion, was often difficult. These factors, plus some early reports that lithium had no antidepressant action, have delayed the recognition of lithium’s role in the treatment of depression. However, a number of studies have now been reported which support the view that lithium is an effective antidepressant in a sub-group of patients. While these studies are not conclusive, the evidence is increasingly convincing. Before discussing the clinical-historical features of lithium-responsive patients, a brief review of some of the evidence for lithium’s antidepressant effect is useful.

Clarification of the relationship between brain serotonin metabolism and cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels is of crucial importance in advancing our understanding of the physiology of these compounds and in providing information about possible metabolic changes in the brains of patients with neurologic and psychiatric disorders. There are two main views regarding this relationship: (i) that most 5-HIAA is excreted directly from the brain into the bloodstream, or (ii) that 5-HIAA first enters the CSF and is then excreted into the blood by bulk flow and via the active transport system of the choroid plexus. Resolution of this problem is of importance to biomedical research because the study of the concentration of 5-HIAA in the CSF is one of the few potential strategies available for gaining information about the metabolism of serotonin (5-HT) in the human brain.

Les taux de Na, K et Mg dans les erythrocytes de 4 hommes sont restes constants lorsque les sujects prenaient des dietes avec des quantites tres differentes de cas cathions. Ce resultat indique que dans l'erythrocyte les concentrations de ces ions ne sont pas modifiees par des variations tres marquees de la quantite des electrolytes ingestes.